Mesalamine suppository

ABSTRACT

The present invention relates to a mesalamine rectal suppository designed to provide improved comfort of use. One embodiment of the invention is a mesalamine rectal suppository containing mesalamine and one or more pharmaceutically acceptable excipients, wherein the drug load of the suppository ranges from 35% to 50%. Another embodiment of the invention is a mesalamine rectal suppository containing from about 850 to about 1150 mg mesalamine and one or more pharmaceutically acceptable excipients, wherein the total weight of the suppository ranges from about 2250 to about 2700 mg. Yet another embodiment of the invention is a mesalamine rectal suppository comprising mesalamine having a tap density ranging from about 600 to about 800 g/L (as measured by USP &lt;616&gt;) and a hard fat having an ascending melting point of 32 to 35.5° C. Methods of preparing and methods of treatment with mesalamine suppositories are also provided. The invention further provides a method of determining a dissolution parameter (such as dissolution rate) of a mesalamine rectal suppository, such as a 1 g mesalamine suppository, by measuring its dissolution with USP Apparatus #2 at 40° C. and a paddle rotation speed of 125 rpm in 0.2 M phosphate buffer at a pH of 7.5.

This application is a continuation of U.S. application Ser. No.12/135,103, filed Jun. 6, 2008, and claims the benefit of provisionalapplication 60/943,029, filed Jun. 8, 2007.

FIELD OF THE INVENTION

The present invention relates to a mesalamine suppository designed toprovide improved comfort of use, a method for manufacturing it, andmethods for treating ulcerative colitis, such as active ulcerativeproctitis, with it as well as a method of measuring a dissolutionparameter of a mesalamine suppository.

BACKGROUND OF THE INVENTION

Inflammatory bowel diseases (IBD), such as Crohn's disease andulcerative colitis (UC), are characterized by chronic, relapsingintestinal inflammation. Crohn's disease and UC are believed to involvea dysregulated immune response to gastrointestinal (GI) tract antigens,a mucosal barrier breach, and/or an adverse inflammatory reaction to apersistent intestinal infection. In normal people, the GI tract luminalcontents and bacteria constantly stimulate the mucosal immune system,and a delicate balance of pro-inflammatory and anti-inflammatory cellsand molecules maintains the integrity of the GI tract, without elicitingsevere and damaging inflammation [MacDermott, R. P., J Gastroenterology,31:907:-916 (1996)]. It is unknown how the IBD inflammatory cascadebegins, but constant GI antigen-dependent stimulation of the mucosal andsystemic immune systems perpetuates the inflammatory cascade and driveslesion formation.

UC is a non-specific inflammatory disease of the colon that is ofunknown cause and is characterized by diarrhea with discharge of mucusand blood, cramping abdominal pain, and inflammation and edema of themucous membrane with patches of ulceration. UC limited to the rectum isknown as ulcerative proctitis. People suffering from chronic UCaffecting the whole colon have an increased risk of colonic cancer.Furthermore, when medical therapy fails, surgical resection of affectedbowel may be necessary.

In patients with more extensive disease, blood loss from the inflamedintestines can lead to anemia, and may require treatment with ironsupplements or even blood transfusions. Although infrequent, the coloncan acutely dilate to a large size when the inflammation becomes verysevere. This condition is called toxic megacolon. Patients with toxicmegacolon are extremely ill with fever, abdominal pain and distention,dehydration, and malnutrition. Unless the patient improves rapidly withmedication, surgery is usually necessary to prevent colon rupture andhigh risk of death.

Mesalamine, 5-aminosalicylic acid (5-ASA), is often used to treat UC andis effective in reducing disease symptoms and the incidence of relapsein UC. While mesalamine is available in oral form, intrarectaladministration of it has several advantages. For example, rectaladministration of a drug avoids some side-effects, such asgastrointestinal disorders, due to oral administration. Lower doses of adrug can be administered rectally to obtain the same therapeutic effectas that attained with a higher dose oral formulation. Since, unlike theGI tract, acids and enzymes scarcely exist in the rectum, the drugremains substantially intact before absorption. Furthermore, because themajority of drug absorbed from the rectum first moves with blood streamswhich do not pass through the liver, less of the absorbed drug ismetabolized and inactivated by the liver in contrast to oraladministration in which the absorbed drug generally moves with bloodstreams which flow through the liver. The absorption of a drug orallyadministered may also be affected by whether it is administered beforeor after each meal or between meals. There is no such food effect whendrugs are administered intrarectally. Intrarectal administration can beperformed even during nausea, vomiting or unconsciousness, or aftersurgical operation.

A 1 g mesalamine suppository of a substantial size (3 g) is currentlymarketed in the U.S. by Axcan Scandipharm Inc. as CANASA® for thetreatment of active ulcerative proctitis.

There is a need for mesalamine suppositories which provide increasedcomfort of use.

SUMMARY OF THE INVENTION

The present inventors have discovered that the size of a mesalaminesuppository can be drastically reduced (for example, by over 20% byweight) and the melting point lowered without a substantial adverseeffect on its dissolution profile or its overall therapeutic efficacy.The combination of a smaller suppository and a lower melting temperatureprovides increased comfort of use. The inventors discovered that thisresult can be obtained by increasing the tap density of the mesalamineand, preferably, also lowering the melting point of the suppositorybase.

Generally when the drug load of a mesalamine suppository is increased,so too is its viscosity. If the viscosity of the mesalamine suspensionis too high, it cannot be cast into a suppository having goodtherapeutic properties. The inventors have surprisingly found that theviscosity of the measlamine suspension can be decreased by increasingthe tap density of the mesalamine.

One embodiment of the present invention is a mesalamine rectalsuppository comprising mesalamine and one or more pharmaceuticallyacceptable excipients, wherein the drug load of the suppository rangesfrom about 35% to about 50% and preferably from about 37% to about 46%.The suppository may include from about 850 to about 1150 mg mesalamine,and preferably includes about 950 mg to about 1050 mg mesalamine (andeven more preferably about 1000 mg mesalamine). The mesalaminesuppository may further include a suppository base, such as hard fat(e.g., hard fat NF).

Another embodiment of the invention is a mesalamine rectal suppositorycomprising from about 850 to about 1150 mg mesalamine and one or morepharmaceutically acceptable excipients, wherein the total weight of thesuppository ranges from about 2250 to about 2700 mg. Preferably, thetotal weight of the suppository ranges from about 2250 to about 2500 mg.The amount of mesalamine in the suppository preferably ranges from about950 mg to about 1050 mg and more preferably is about 1000 mg. Themesalamine suppository may further include a suppository base, such ashard fat (e.g., hard fat NF).

The mesalamine in each of the aforementioned suppositories preferablyhas a tap density ranging from about 600 to about 800 g/L (as measuredby USP <616>). According to a preferred embodiment, the mesalamine inthe aforementioned suppositories is dispersed in a low meltingsuppository base (i.e., a suppository base having an ascending meltingpoint of no more than 35.5° C.). A preferred low melting suppositorybase is hard fat having an ascending melting point of 32 to 33.5° C.(e.g., Witepsol® H 12 available from Sasol Germany GmbH of Witten,Germany). Another suitable low melting suppository base is hard fathaving an ascending melting point of 33.5 to 35.5° C. (e.g., Witepsol®H-15 available from Sasol Germany GmbH). The dispension is preferablysubstantially homogenous.

Yet another embodiment of the invention is a mesalamine rectalsuppository comprising mesalamine having a tap density ranging fromabout 600 to about 800 g/L (as measured by USP <616>) and a hard fathaving an ascending melting point of 32 to 35.5° C. Typically, themesalamine is dispersed in the hard fat. According to one preferredembodiment, the hard fat has an ascending melting point of 32 to 33.5°C. Preferably, such a dispension is substantially homogenous. The weightratio of mesalamine to hard fat preferably ranges from about 1:2 toabout 1:1.25.

Preferably, the aforementioned suppositories each release at least about75% by weight of the mesalamine contained in the suppository within 2hours of dissolution as measured with USP Apparatus #2 at 40° C., apaddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphatebuffer at a pH of 7.5. In one embodiment, at least about 80, 90, or 95%by weight of the mesalamine is dissolved within 2 hours. According toanother embodiment, at least about 80 or 90% by weight of the mesalamineis dissolved within 1 hour. According to yet another embodiment, atleast 90% by weight of the mesalamine is dissolved within 30 minutes.

Yet another embodiment is a method of treating ulcerative colitis, suchas active ulcerative proctitis, in a patient in need thereof byadministering to the patient a mesalamine rectal suppository of thepresent invention. Preferably, the mesalamine suppository isadministered once a day and more preferably once a day at bedtime. Thesuppository is also preferably retained for one to three hours orlonger, if possible. The treatment can be brief, for example, once dailyfor three to twenty-one days, or can be longer, for example, once dailyfor three to six weeks.

Yet another embodiment is a method of determining a dissolutionparameter (such as dissolution rate or amount of drug dissolved after aspecified period of time) of a mesalamine rectal suppository, such as a1 g mesalamine suppository, by measuring its dissolution with USPApparatus #2 at 40° C. and a paddle rotation speed of 125 rpm in 0.2 Mphosphate buffer at a pH of 7.5. According to a preferred embodiment, asinker is lightly coiled around the suppository, for example with only 3turns of wire helix. This dissolution method produces results which aresignificantly more reliable and less variable than those produced byother dissolution methods, such as methods 1 and 3 discussed in Examples1 and 2.

Yet another embodiment is a method of preparing a mesalamine rectalsuppository by (A) providing a mesalamine rectal suppository, and (B)measuring the dissolution rate of the suppository with USP Apparatus #2at 40° C. and a paddle rotation speed of 125 rpm in 0.2 M phosphatebuffer at a pH of 7.5. According to a preferred embodiment, a sinker islightly coiled around the suppository, for example, with only 3 turns ofwire helix. Step (B) may include determining whether the suppositoryreleases at least about 75% by weight of the mesalamine within 2 hoursof dissolution.

Yet another embodiment is a method of preparing a batch of mesalaminerectal suppositories (i.e., 2 or more suppositories) by (A) providing abatch of mesalamine rectal suppositories; and (B) measuring thedissolution rate of at least one suppository from the batch with USPApparatus #2 at 40° C. and a paddle rotation speed of 125 rpm in 0.2 Mphosphate buffer at a pH of 7.5. According to a preferred embodiment, asinker is lightly coiled around the suppository, for example, with only3 turns of wire helix. Preferably, step (B) includes determining whetherthe suppository releases at least about 75 or 80% by weight of themesalamine within 2 hours of dissolution (Q=75% as described in USP 711(30^(th) Ed.), the section entitled “immediate-release dosage forms”).If the suppository does not meet the dissolution criterion, the batch ofsuppositories can be discarded.

Yet another embodiment is a method of preparing a mesalamine rectalsuppository by preparing the suppository from mesalamine having a tapdensity ranging from about 600 to about 800 g/L with a suppository base,such as a hard fat, having an ascending melting point of 32 to 33.5° C.The inventors have found that the viscosity of a molten mixturecontaining mesalamine varies significantly depending on the tap densityof the mesalamine used to form the molten mixture. A molten mixturehaving a high viscosity (e.g., greater than 5000 cps) has been found tohave flow problems during suppository filling and caused small entrappedair bubbles to be molded into the surface of the suppository resultingin an aesthetically less desirable product. The suppository may, forexample, be prepared by (A) mixing the mesalamine having theaforementioned tap density with a suppository base having theaforementioned melting point, and (B) molding the mixture.

According to one embodiment, the mesalamine suppository is prepared by(A) melting the suppository base, e.g., to form a molten solution, (B)adding mesalamine to the melted suppository base, and (C) molding themixture.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the viscosity of the molten mixtures preparedin Example 3 versus the tap densities of the mesalamine used to preparethe molten mixtures.

FIG. 2 is a graph showing the viscosity of the molten mixtures preparedin Example 4 versus the tap densities of the mesalamine used to preparethe molten mixtures.

FIG. 3 is a graph showing the viscosity of the molten mixtures preparedin Examples 3 and 4 versus the tap densities of the mesalamine used toprepare the molten mixtures.

FIGS. 4-9 show the dissolution profiles of mesalamine suppositorieshaving drug loads of 33, 37, and 42% prepared from mesalamine having atap density of 680 or 730 g/L and hard fat having an ascending meltingpoint of 32 to 33.5° C. (Witepsol® H-12) or 33.5 to 35.5° C. (Witepsol®H-15).

FIG. 10 shows the dissolution profiles of mesalamine suppositorieshaving drug loads of 42 and 44% prepared from mesalamine having a tapdensity of 730 g/L and hard fat having an ascending melting point of 32to 33.5° C. (Witepsol® H-12).

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “mesalamine” refers to 5-aminosalicylic acid (5-ASA). Accordingto one embodiment, the mesalamine has the following particle sizedistribution: X10 of about 5 to about 11 μm, X50 of about 25 to about 45μm, and X90 of about 85 to about 100 μm.

The term “drug load” refers to the weight percentage of mesalamine basedon the total weight of the suppository.

As used herein, the term “patient” refers to any mammal and preferably ahuman. The patient to be treated with mesalamine may in fact be anypatient of the human population, male or female, which may be dividedinto children, adults, or elderly. Any one of these patient groupsrelates to an embodiment of the invention.

As used herein, the term “treating” refers to preventing or delaying theappearance of clinical symptoms of a disease or condition in a patientthat may be afflicted with or predisposed to the disease or condition,but does not yet experience or display clinical or subclinical symptomsof the disease or condition. “Treating” also refers to inhibiting thedisease or condition, i.e., arresting or reducing its development or atleast one clinical or subclinical symptom thereof. “Treating” furtherrefers to relieving the disease or condition, i.e., causing regressionof the disease or condition or at least one of its clinical orsubclinical symptoms. The benefit to a patient to be treated is eitherstatistically significant or at least perceptible to the patient and/orthe physician.

Symptoms of active ulcerative proctitis include, but are not limited to,abdominal pain, diarrhea, rectal bleeding, sensation of incompleteemptying of the bowels, weight loss, fever, loss of appetite, tiredness,and other more serious complications, such as dehydration, anemia andmalnutrition. A number of such symptoms are subject to quantitativeanalysis (e.g. weight loss, fever, anemia, etc.). Some symptoms arereadily determined from a blood test (e.g. anemia).

Unless otherwise specified, tap density is measured by the USP tappeddensity test <616>.

Formulations

The mesalamine (e.g., in powder form) is typically dispersed in asuppository base, such as hard fat. The suppository base can be an oilyor fatty base. Conventional suppository bases which may be employedinclude theobroma oil, hard fats, glycerides of fatty acids,glycerol-gelatin bases, and mixtures thereof. Suitable hard fat basesinclude, but are no limited to, esterified mixtures of mono-, di- andtriglycerides which are obtained by esterification of fatty acids(European Pharmacopoeia, 3rd edition 1997, Deutscher Apotheker VerlagStuttgart. p. 1022; The United States Pharmacopoeia, USP 23, NF18). Suchhard fats are commercially available, for example, under the nameWitepsol® (e.g. Witepsol® H12). A preferred suppository base is hard fat(e.g., hard fat NF).

Preferred hard fat bases include, but are not limited to, hard fatscontaining a mixture of mono-, di- and triglycerides of saturated C₉₋₁₈fatty acids. The hard fat base can comprise hard fats obtained byesterification of fatty acids of vegetable origin with glycerol, amacrogol ether containing 20 to 24 oxyethylene groups in thepolyoxyethylene chain, e.g., polyoxyl-20-cetostearyl ether, andglycerides, e.g., glyceryl ricinoleate.

Other suitable suppository bases include, but are not limited to, cacaobutter, lauric oil, beef tallow, hard fat, and any combination of any ofthe foregoing.

The drug load of the suppository is preferably 37 to 50%. According toone embodiment, the drug load ranges from about 37 to about 46%.According to another embodiment, the drug load ranges from about 39 toabout 45%. According to yet another embodiment, the drug load rangesfrom about 41 to about 43%. For example, the suppository can containabout 1000 mg mesalamine dispersed in about 1300 to about 1500 mg of asuppository base (preferably hard fat).

The total weight of the suppository preferably ranges from about 2250 toabout 2700 mg and more preferably from about 2250 to about 2500 mg.According to one embodiment, the suppository has a total weight rangingfrom about 2300 mg to about 2500 mg.

The suppository is preferably smooth torpedo-shaped.

The melting point of the suppository is generally sufficient to melt inthe patient's body, and is typically no more than about 37° C.

Methods of Preparation

The mesalamine suppository of the present invention may be prepared asfollows. The mesalamine is dispersed in a suppository base in moltenform, which is then poured into a suitable mould, such as a PVC,polyethylene, or aluminum mould. For example, the mesalamine may bedispersed in the suppository base at a temperature of from about 35° C.to about 50° C. and preferably from about 40° C. to about 44° C. Themesalamine can be milled or sieved prior to incorporation into thesuppository base.

If desired, further pharmaceutically acceptable auxiliaries, such as,for example, stabilizers, consistency-improving additives or auxiliarieswhich bring about a uniform distribution of the mesalamine in thesuppository base, can be added. Optionally the suppositories may becoated, prior to packing, for example with cetyl alcohol, macrogol orpolyvinyl alcohol and polysorbates to increase disintegration time orlubrication or to reduce adhesion on storage.

Preferably, the viscosity of a sample of the molten mesalaminedispersion is determined in-process for quality control. For example,the viscosity cut off may be about 5000 to about 10000 cps. According toone embodiment, batches of molten mesalamine dispersion having aviscosity of about 10000 cps or less would be considered acceptablewhile those having a viscosity over 10000 cps would not (and, therefore,may be discarded). According to another embodiment, batches of moltenmesalamine dispersion having a viscosity of about 5000 cps or less wouldbe considered acceptable.

The tap density of the mesalamine used to prepare the molten mesalaminedispersion is also preferably monitored before production to ensure thatthe tap density of the mesalamine is at least about 600 g/L andpreferably from about 600 to about 800 g/L. Preferably, the mesalamineis not in the form of granules suitable for compaction into tablets.Rather, the mesalamine is preferably in the form of a powder ofunagglomerated needle-shape crystals.

A sample suppository from each batch of suppositories produced ispreferably tested by the dissolution method of the present invention forquality control. According to a preferred embodiment, a sample from eachbatch is tested to determine whether at least about 75 or 80% by weightof the mesalamine dissolves within 2 hours.

Methods of Treatment

The mesalamine suppository can be administered to treat ulcerativecolitis, such as active ulcerative proctitis, in a patient in needthereof. Preferably, the mesalamine suppository is administered insufficient quantity and frequency to reduce the symptoms of ulcerativecolitis.

The mesalamine suppository can also be administered prophylactically toa patient at risk for ulcerative colitis (such as active ulcerativeproctitis). Preferably, the mesalamine suppository is administered insufficient quantity and frequency to delay or prevent the onset ofsymptoms of ulcerative colitis (e.g., to delay or prevent the onset ofabdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss ofappetite, dehydration, anemia, or malnutrition, or any combinationthereof).

In the above methods, the mesalamine suppository is preferablyadministered once a day and more preferably once a day at bedtime. Thesuppository is also preferably retained for one to three hours orlonger, if possible. The treatment can be brief, for example, once dailyfor three to twenty-one days, or can be longer, for example, once dailyfor three to six weeks.

The following examples illustrate the invention without limitation. Allpercentages are by weight unless otherwise indicated.

EXAMPLE 1

The dissolution profiles of 1000 mg mesalamine suppositories (such asthose prepared according to the procedure described below) weredetermined by three different methods (shown in Table 1 below using USPApparatus #2). As discussed below, only the dissolution method of thepresent invention (method 2) produced consistent results.

TABLE 1 Parameter Method 1 Method 2 Method 3 Phosphate buffer 0.05 M 0.2M 0.2 M Temperature 37° C. 40° C. 37° C. Paddle rotation speed 100 rpm125 rpm 100 rpm Sinker turns 7 turns 3 turns 3 turns pH 7.5 7.5 7.5Preparation of 1000 mg Mesalamine Suppositories

1000 mg mesalamine suppositories were prepared by the followingprocedure. Add 200.0 kg of hard fat NF (Witepsol® 15) to a mix tank.Begin heating the batch to 58-62° C. by recirculating steam through thetank jacket. The target temperature is 60° C. Begin mixing with thesweeps at 12 Hz as the product begins to melt. Continue heating to58-62° C. (target 60° C.). Mix until the product is completely molten,increasing the sweeps to 60 Hz as the product melts. Mix for a minimumof 30 minutes, maintaining the temperature at 58-62° C. using the hotbox (target 60° C.). Adjust the temperature of the batch to 40-44° C. byrecirculating tap water at approximately 34-40° C. through the jacket.Maintain the batch at this temperature using the hot box (target 42°C.). While adjusting the temperature, shut off the sweeps, install theprop mixer with one 7″×7″ blade and restart the sweeps to 60 Hz. Beginmixing with the prop at 12 Hz and adjust the sweeps to 30 Hz.

Slowly add 100.0 kg of mesalamine poswer USP to the mix tank. During theaddition of the powder, slowly increase the sweeps to 35 Hz and the propto 35 Hz as the product level in the tank increases, minimizingaeration. The addition of the powder must be performed over a 35 to 60minute interval. The powder must be completely dispersed prior tomixing.

Mix for a minimum of 60 minutes. During the mix period, flush productthrough the bottom valve using a large pot. Continue flushing throughoutthe mixing interval until product appears visually uniform. Return theproduct to the mix tank.

Adjust the temperature of the batch to 43-45° C. by recirculating tapwater at approximately 50-55° C. through the tank jacket or use the hotbox, if necessary. Perform in-process sampling from the bottom valve ofthe tank taking approximately 600 g in a plastic beaker. Hook up the hotbox and set it to hold the temperature of the batch at 43-45° C. Adjustthe sweeps to 30-36 Hz and prop to 20-30 Hz to prevent aeration of theproduct.

Fill each mould. Remove 1 suppository per filling head (14 consecutivesuppositories) every 25-35 minutes of operation. Fill weights ofindividual suppositories should be between 2.85 and 3.15 g.

Results

The dissolution profile of the 1000 mg mesalamine suppositories weredetermined by methods 1 and 2. The results are shown in Tables 2 and 3,respectively.

TABLE 2 Time Sample 1 Sample 2 Sample 3 10 min 10.5 11.8 11.3 20 min22.4 20.9 21.8 30 min 32.9 27.4 29.3 60 min 54.6 42.8 44.5 90 min 66.854.2 56.3 120 min  77.2 63 65.9 Average and SD 68.70 (SD = 7.50) (after120 min)

TABLE 3 Time #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 Average SD  60 min92.2 93 96.8 93.7 93.4 93.2 92.8 93.8 84 97.2 94.4 96.6 93.4 3.4 120 min97.3 97.6 98.1 97.9 95.5 98.6 98.1 97.9 97.9 98.1 97.9 98.4 97.8 0.8 240min 97.5 98.2 97.7 97.2 97 98.6 98.1 97.3 97.8 97.3 97.2 97.8 97.6 0.5(SD = standard deviation)

The variability in the dissolution values after 120 minutes wassignificantly lower when measured by method 2 than when measured bymethod 1.

This low variability was further shown by dissolution tests usingmethods 2 and 3 performed on 1000 mg suppositories stored under normal(25° C. and 60% relative humidity) and accelerated (30° C. and 60%relative humidity) storage conditions. The results are provided inTables 4 and 5, respectively, and show that method 2 providesreproducible dissolution values with minimal intra-lot andbatch-to-batch variability.

TABLE 4 Time #1 #2 #3 #4 #5 #6 Average (%) SD Batch 1 (23.5 months, 25°C./60% RH)  60 min 97.8 96.8 98 99.2 98.2 98.6 98.1 0.8 120 min 98.798.9 98.5 99.2 98.3 98.2 98.6 0.4 240 min 98.3 98.5 98.1 98.6 97.5 987.798.1 0.4 Batch 2 (14.5 months, 25° C./60% RH)  60 min 97.6 97.5 98.298.2 97.6 97.1 97.7 0.4 120 min 97.1 97.5 97.9 97.9 98.3 97.2 97.7 0.5240 min 97.3 96.7 97.4 97.4 97.7 96.9 97.2 0.4 Batch 3 (4 months, 25°C./60% RH)  60 min 98.5 96.7 91 92.2 96.7 98.2 95.6 3.2 120 min 98.998.7 94.4 98.7 98.7 98.6 98.0 1.8 240 min 98.5 98.2 96 97.3 97.7 97.897.6 0.9 Batch 4 (2.5 months, 25° C./60% RH)  60 min 99.3 99.5 100.399.3 98.7 99.6 99.5 0.5 120 min 98.8 98.9 99.9 99.4 98.4 99.6 99.2 0.6240 min 98.5 98.9 99.4 98.6 97.8 99.1 98.7 0.6 Batch 5 (4.5 months, 25°C./60% RH)  60 min 100.8 101.7 101.3 101.4 101.3 101.4 101.3 0.3 120 min100.2 101.4 100.9 101 101.1 101.8 101.1 0.5 240 min 100.2 100.5 100.5100.5 100.8 101.1 100.6 0.3 Batch 6 (4.5 months 25° C./60% RH)  60 min99.7 99.8 99.3 101.1 100 100.3 100.0 0.6 120 min 98.7 99.9 99.8 100.8100.1 100.1 99.9 0.7 240 min 98.5 99.4 99.7 100.6 99.8 99.4 99.6 0.7Batch 7 4.5 months, 25° /60% RH)  60 min 99.7 99.9 99.2 100.5 99.4 99.699.7 0.5 120 min 100 99.7 99.6 100.4 99.1 99.7 99.8 0.4 240 min 99.7 9999 99.5 98.7 98.8 99.1 0.4 Batch 8 (3.5 months, 30° C./60% RH)  60 min100.8 100.3 100.7 101 101 100.7 100.8 0.3 120 min 100.6 99.9 100.5 100.6100.6 100.3 100.4 0.3 240 min 99.9 99.2 99.9 100 100 99.5 99.8 0.3 Batch9 (3.5 months, 30° C./60% RH)  60 min 100 99.9 100.2 99.7 99.8 99.8 99.90.2 120 min 99.7 99.4 100 99.4 100 99.5 99.7 0.3 240 min 99.3 98.8 99.499 99.2 98.9 99.1 0.2 Batch 10 (3.5 months 30° C./60% RH)  60 min 99.398.9 99.9 99.8 99.6 99.3 99.5 0.4 120 min 99.6 98.7 99.1 99.6 99.1 99.799.3 0.4 240 min 99.1 98.4 98.6 99.2 98.7 99.1 98.9 0.3

TABLE 5 Sample No. (within batch) Batch 1 2 3 4 5 6 Average SD 11 101.5102.4 102.5 101.5 100.9 100.6 101.6 0.8 6 months at 25° C./60% RH 12101.3 100.3 101.3 102.3 100.3 100.0 100.9 0.9 6 months at 25° C./60% RH13 100.4 99.7 98.6 100.3 98.8 99.8 99.6 0.8 6 months at 25° C./60% RH 1498.2 99.3 98.9 97.2 99.1 98.8 98.6 0.8 25 months at 25° C./60% RH 1592.4 98.4 97.6 97.3 96.7 92.0 95.7 2.8 16 months at 25° C./60% RH 1698.4 96.4 95.5 96.8 99.6 96.9 97.3 1.5 5 months at 25° C./60% RH 17 9998 97 100 99 81 95.7 7.3 23 months at 25° C./60% RH 18 101 103 100 103100 102 101.5 1.4 23 months at 25° C./60% RH 19 101 102 101 103 100 102101.5 1.0 20 months at 25° C./60% RH 20 97 102 97 95 99 96 97.7 2.5 6months at 30° C./60% RH 21 94 94 72 81 91 106 89.7 11.8 6 months at 30°C./60% RH 22 85 92 93 89 94 75 88.0 7.2 6 months at 30° C./60% RH 23 8590 97 91 96 85 90.7 5.2 6 months at 30° C./60% RH 24 75 50 66 72 61 4060.7 13.4 6 months at 30° C./60% RH 25 73 97 60 89 87 81 81.2 13.1 6months at 30° C./60% RH

Samples from the three batches exhibiting the highest variability whenmeasured according to method 3, i.e., batches 21, 24 and 25, were testedby method 2 for comparison. The results are shown in Table 6.

TABLE 6 Sample No. (within batch) Batch 1 2 3 4 5 6 Average SD 21 100100 100 100 101 101 100.3 0.52 24 101 101 101 101 101 102 101.2 0.41 25100 100 101 100 99 100 100.0 0.63

These results show that method 2 produced more reliable and lessvariable dissolution results than method 3.

EXAMPLE 2

The dissolution profiles of the 1000 mg mesalamine suppositoriesprepared in Example 1 were determined according to method 1 described inExample 1.

The results are shown in Table 7 below.

TABLE 7 1000 mg suppository At 120 min, Average: 73% + 10.3 (SD) Range:54.8%-97.1%

EXAMPLE 3

The following experiment was conducted to determine if the tap densityof the mesalamine powder starting material significantly affected theviscosity of the molten mixture used to form the suppository. Generally,a molten mixture having a viscosity greater than about 5000 to about10000 cps was found to have flow problems during suppository filling andcaused small entrapped air bubbles to be molded into the surface of thesuppository resulting in an aesthetically less desirable product.

The tap density of several lots of mesalamine were determined by USPtapped density test <616> and are shown in Table 8 below.

TABLE 8 Mesalamine Lot Tapped Density (g/ml) A 0.81 B 0.72 C 0.68 D 0.39E 0.68 F 0.46 G 0.60

Molten mixtures were prepared by the procedure described in Example 1using mesalamine lots A, B, and E. The molten mixtures had theviscosities reported in Table 9 below.

TABLE 9 Molten Mixture Mesalmine Mesalamine Tap Density Viscosity LotNo. Lot (g/ml) (cps) 1 A 0.81 429 2 B 0.72 468 3 E 0.68 1010

Molten mixtures prepared from combinations of mesalamine lots C-G wereprepared and had the viscosities reported in Table 10 below. Theindividual tap densities of each mesalamine lot were used to calculate acomposite tapped density (CTD) based on the amount of each lot. Thecalculated CTD can be expressed by the following equation:(CDF)₁+(CDF)₂+ . . . (CDF)_(n) =CTDwhere CTD=composite tapped density; CDF=contributed density factor=% oftotal drug used/100×TD; TD=measured tapped density; and n=number of druglots used.

TABLE 10 Molten Mixture Mesalamine Measlamine TD CTD Viscosity Lot No.Lot used (Kg) (g/ml) (g/ml) (cps) 4 C 82.5 0.68 D 17.5 0.37 0.62 1680 5D 61.0 0.37 E 17.0 0.68 F 22.0 0.46 0.44* 13300 6 G 100.0 0.60 0.60 1730*Note: Accuracy of the CTD of the 3 mesalamine lots used was confirmedby measuring the tap density of a separate mesalamine powder blend atthe same ratio. The result was 0.43 g/ml compared to 0.44 g/ml.

The density-viscosity data from Tables 9 and 10 were combined andplotted (FIG. 1) to assess the correlation for these two parameters.These data show a definite rank-order inverse relationship, with acorrelation coefficient of 0.9743. Notably, a reduction in the CTD from0.60 g/ml to 0.44 g/ml resulted in a 7 fold increase in viscosity from1730 cps to 13300 cps (see molten mixture lot nos. 5 and 6 in Table 10).

EXAMPLE 4

The procedure described in Example 3 was repeated with mesalamine lotnos. 1-8 shown in Table 11 below. The results are shown in Table II andFIG. 2. From the correlation curve in FIG. 2, a viscosity of 5000 cpscorresponds to a tap density of about 0.50 g/ml.

TABLE 11 Mesalamine Lot No. Tap Density (g/ml) Viscosity (cps) 1 0.4513845 2 0.53 1755 3 0.44 19500 4 0.36 37100 5 0.40 47500 6 0.40 26910 70.36 37830 8 0.37 33735

The correlation of density to viscosity is essentially rank-order anddemonstrates an inverse relationship of the two parameters (correlationcoefficient=0.8803).

The tap density and viscosity data from Examples 3 and 4 (Tables 9-11)were combined and are shown graphically in FIG. 3. The combined dataclearly show the strong correlation (correlation coefficient=0.9343)between the tap density of mesalamine powder and its effect on thein-process viscosity of the drug-hard fat dispersions.

EXAMPLE 5

1 g mesalamine suppositories using Witepsol® H-15 or Witepsol® H-12(hard fat NF) as the suppository base were prepared by the proceduredescribed in Example 1 at drug loads of 33, 37, 42, and 44%. All thesuppositories released at least 75% by weight of the mesalaminecontained in the suppository within 2 hours of dissolution as measuredwith USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5 (method #2 ofTable #1).

FIGS. 4 and 5 show the dissolution profiles of mesalamine suppositorieshaving drug loads of 33, 37, and 42% prepared from mesalamine having atap density of 680 g/L and Witepsol® H-15.

FIG. 6 shows the dissolution profiles of mesalamine suppositories havingdrug loads of 33, 37, and 42% prepared from mesalamine from Supplier 2,Grade B, having a tap density of 730 g/L and Witepsol® H-15.

The in-process molten mixtures of mesalamine and hard fat used in thepreparation of the suppositories described above with respect to FIGS. 4to 6 had the viscosities reported in Table 12 below. Suppositories couldnot be made from Grades C and D from supplier 2. Grades C and D weredesigned for compression of the mesalamine into tablets and were foundto be unsuitable for the preparation of a suspension in hard fat asrequired for the preparation of the suppository.

TABLE 12 Tap Dispersion Density Drug Load Viscosity Source g/L (% w/w)(Cps) Supplier 1 0.68 33 694 37 1131 42 2512 Supplier 2, grade A 0.68 33595 37 1084 42 2553 Supplier 2, grade B 0.73 33 515 37 845 42 1911Supplier 2, grade C 0.58 33 Too Viscous Supplier 2, grade D 0.91 33 PoorDispersion

FIG. 7 shows the dissolution profiles of mesalamine suppositories havinga drug load of 42% prepared from mesalamine having a tap density of 680g/L (supplied by Suppliers 1 and 2) or 730 g/L (Supplier 2, grade B) andWitepsol® H-15.

FIG. 8 shows the dissolution profiles of mesalamine suppositories havingdrug loads of 33% and 42% prepared from mesalamine having a tap densityof 680 g/L from supplier 1 and Witepsol® H-12 (ascending melting pointof 32 to 33.5° C.) or Witepsol® H-15 (ascending melting point of 33.5 to35.5° C.). It also compares suppositories having drug loads of 42%prepared with a mesalamine from supplier 2 having a tap density of 730g/ml manufactured using Witepsol® H-12 (ascending melting point of 32 to33.5° C.).

FIG. 9 shows the dissolution profiles of mesalamine suppositories havinga drug load of 42% prepared from mesalamine having a tap density of 680g/L (Supplier 1) or 730 g/L (Supplier 2, grade B) and Witepsol® H-12 orWitepsol® H-15.

FIG. 10 shows the dissolution profiles of mesalamine suppositories froma larger scale batch having drug loads of 42 and 44% prepared frommesalamine having a tap density of 730 g/L (Supplier 2, grade B) andWitepsol® H-12.

EXAMPLE 6 High Density 1000 mg Mesalamine Suppositories

1 g mesalamine suppositories, each containing 1000 mg mesalamine (USP)and 1381 mg Witepsol® H-12 (hard fat NF), were prepared according to thefollowing procedure.

The hard fat (Witepsol® H-12, 65.25 kg) is melted by charging it into akettle, which is operated in automatic mode with a tank temperature of75° C., a melting temperature of 60° C., a cooling water temperature of48° C., a cooling air temperature of 44° C., a holding a T melting of 45minutes, a mixing at T melting of 15 minutes, and a holding at 256 rpmfor 60 minutes. When the temperature reaches 40-44° C., the mixing speedis between 60-80 rpm, and the water heating tank temperature is 71-79°C., the mesalamine from Supplier 2, grade Bis slowly added over a periodof 50 to 70 minutes with constant mixing at 230-270 rpm. The solution isthen mixed for 55 to 65 minutes (set point of 60 minutes) at 230-270rpm. After the mixing time, the mixing speed is adjusted to 168-180 rpm(set point of 175 rpm).

Moulds are then filled, each mould containing 2.33-244 g of thesolution. The moulds are then cooled for 5 to 10 minutes at 20° C.

1 g suppositories heat sealed in PVC/PE containers (2.3 mL capacity percavity) were stored for at 25±2° C. and 60±5% relative humidity for 3months. The suppositories were found to be stable and release at least80% by weight of the mesalamine contained in the suppository within 2hours of dissolution as measured with USP Apparatus #2 at 40° C., apaddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphatebuffer at a pH of 7.5.

All non-patent references, patents and patent applications cited anddiscussed in this specification are incorporated herein by reference intheir entirety and to the same extent as if each was individuallyincorporated by reference.

1. A mesalamine rectal suppository comprising from about 850 to about1150 mg of mesalamine and a fatty base, wherein the mesalamine has a tapdensity ranging from about 600 to about 800 g/L (as measured by USP<616>), the drug load of the suppository ranges from 35% to 46%, and thesuppository releases at least 75% by weight of the mesalamine within 2hours of dissolution as measured with USP Apparatus #2 at 40° C., apaddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphatebuffer at a pH of 7.5.
 2. The mesalamine suppository of claim 1, whereinthe amount of mesalamine ranges from about 950 to about 1050 mg.
 3. Themesalamine suppository of claim 1, wherein the fatty base is hard fat.4. The mesalamine suppository of claim 1, wherein the fatty base has anascending melting point ranging from 32 to 33.5° C.
 5. The mesalaminesuppository of claim 1, wherein the fatty base has an ascending meltingpoint from 33 to 35.5° C.
 6. The mesalamine suppository of claim 4, thebase is hard fat.
 7. The mesalamine suppository of claim 5, the fattybase is hard fat.
 8. The mesalamine suppository of claim 1, wherein thedrug load ranges from about 39 to about 45%.
 9. The mesalaminesuppository of claim 8, wherein the drug load ranges from about 41 toabout 43%.
 10. The mesalamine suppository of claim 1, wherein thesuppository releases at least 80% by weight of the mesalamine within 2hours of dissolution as measured with USP Apparatus #2 at 40° C., apaddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphatebuffer at a pH of 7.5.
 11. The mesalamine suppository of claim 1,wherein the suppository releases at least 80% by weight of themesalamine within 1 hour of dissolution as measured with USP Apparatus#2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in0.2 M phosphate buffer at a pH of 7.5.
 12. The mesalamine suppository ofclaim 1, wherein the suppository releases at least 90% by weight of themesalamine within 30 minutes of dissolution as measured with USPApparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinkerturns in 0.2 M phosphate buffer at a pH of 7.5.
 13. A method of treatingactive ulcerative proctitis in a patient in need thereof comprisingadministering the mesalamine rectal suppository of claim 1 to thepatient.
 14. The method of claim 13, wherein the mesalamine rectalsuppository is administered once a day.
 15. The method of claim 14,wherein the mesalamine rectal suppository is administered once a day atbedtime.
 16. The mesalamine suppository of claim 1, wherein thesuppository is a moulded suppository.